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Gene that triggers 'memory extinction' discovered

Many of us are the bearers of "bad" memories that, to this day, continue to affect our lives. Now, scientists say they have discovered a gene essential for "memory extinction," the process by which our brain replaces older memories with new experiences.

Researchers from the Massachusetts Institute of Technology (MIT) say the discovery could help people suffering from post-traumatic stress disorder (PTSD) by replacing "fearful" memories with more positive associations.

The gene, Tet1, has been found to play a critical role in memory extinction by controlling a small group of other genes that are necessary for the process.

For the study, published in the journal Neuron, the research team experimented on mice who had the Tet1 gene "knocked out," as well as on mice who had normal levels of the gene.

In order to measure the mice's ability to abolish memories, the mice were "conditioned" to fear a certain cage in which they received a small electric shock. Once the memory of the "cage shock" was formed, the mice were placed into the cage, but the researchers did not give them the shock.

Tet1 triggers 'memory extinction'

The researchers found that after a period of time, mice with normal Tet1 levels appeared to lose their fear of the cage, indicating that new memories replaced the old ones.

"What happens during memory extinction is not erasure of the original memory. The old trace of memory is telling the mice that this place is dangerous. But the new memory informs the mice that this place is actually safe. There are two choices of memory that are competing with each other."

However, the researchers add that the mice without the Tet1 gene remain fearful and are unable to extinguish the memory.

The team carried out another set of experiments that tested the mice's spatial memory.

These experiments showed that the mice without the Tet1 gene had the ability to learn to navigate a water maze, but they were unable to extinguish the memory of how to navigate the maze, further supporting the findings of the previous experiment.

Tet1 removes DNA methylation

The researchers explain that the Tet1 and other Tet proteins help to regulate the modifications of DNA that determine whether a certain gene will be expressed or not.

Tet1 alters the levels of DNA methylation - a modification that controls access to genes. High methylation levels prevent genes from being expressed, while low methylation levels allow them to be "switched on."

Tet1 and Tet proteins were found to remove DNA methylation, after the mice without Tet1 showed significantly lower levels of hydroxymethylation - the process leading to the removal of methylation - in both the hippocampus and cortex of the brain. These areas are key for learning and memory.

Demethylation higher in early memory genes

The researchers found that demethylation was most significant in a group of 200 genes, particularly a small subset referred to as "immediate early genes" - critical for memory formation.

In the mice without the Tet1 gene, it was found that immediate early genes were highly methylated, meaning it would be difficult for these genes to be expressed.

Previous research from MIT showed that an immediate early gene called Npas4 regulates other immediate early genes. In this study, the researchers found that in the promoter region of the Npas4 gene, methylation levels in mice without the Tet1 gene was almost 60%, compared with 8% in mice who had the Tet1 gene.

"It's a huge increase in methylation, and we think that is most likely to explain why Npas4 is so drastically downregulated in the Tet1 knockout mice," notes Prof. Tsai.

Matthew Lattai, associate professor of behavioral neuroscience at Oregon Health and Science University, who was not a part of the study, says the findings could pave the way for treatments for PTSD:

"By demonstrating some of the ways that regulatory genes are methylated in response to Tet1 knockout and behavioral experience, the authors have taken an important step in identifying potential pharmacological treatment targets for disorders such as PTSD and addiction."

Furthermore, the research team also discovered why mice without the Tet1 gene still have the ability to learn new tasks.

They found that during fear conditioning, the methylation of the Npas4 gene reduced to 20% - a level low enough for Npas4 to be expressed, therefore creating new memories.

The team hypothesize that the mice's fear is so strong that it may trigger other demethylation proteins, such as Tet2 or Tet3.

Overall, the researchers say that their findings suggest there is a threshold level needed in order for methylation to take place, and that Tet1 is responsible for maintaining low methylation to make sure that the genes needed for memory formation are ready to be "turned on" when needed.

Further research from the team will involve searching for ways to artificially increase Tet1 levels and seeing whether this could "boost" memory extinction. Additionally, they plan to determine the effects of erasing all Tet genes.

Meelad Dawlaty of MIT's Whitehead Institute, adds:

"This will not only help us further delineate epigenetic regulation of memory formation and extinction, but will also unravel other potential functions of Tets and methylation in the brain beyond memory extinction."

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